The discovery of new and more selective anticancer agents is of fundamental importance in our struggle against cancers. Recently, the drug Lometrexol was discovered to exhibit excellent antitumor activity against a range of solid tumors, in addition to being active against tumors that have become resistant to methotrexate (MTX), a commonly used antifolate drug used in cancer chemotherapy. Lometrexol has shown some remarkable results in animal trials (complete inhibition of tumor growth at 6.25 mg/kg per day for ten days without evidence of host toxicity up to 100 mg/kg per day). The primary site of action of Lometrexol has been shown to be inhibition of the enzyme glycinamide ribonucleotide formyltransferase (GARFT) which plays a critical role in de novo purine biosynthesis. Lometrexol is currently in clinical trials for the treatment of human neoplastic diseases. However, one study has indicated that the observed selectivity of this drug in animal experiments was not apparent in humans and the compound was reported to show severe toxicity. It is, therefore, of considerable importance to prepare structurally modified analogs of Lometrexol with the aim of discovering a more selective, less toxic, agent for the treatment of human cancers. We propose a versatile synthetic route to twelve selected pyrimidoazepine-base folates, structurally related to Lometrexol, using intramolecular 1, 3-dipolar cycloaddition chemistry as a key step. Testing these compounds in mammalian GARFT assays should enhance our knowledge of the structure-activity requirements of folate antimetabolites with regard to this enzyme. Our targets will be further evaluated in appropriate tumor cell culture assays to determine their potential as antitumor agents.